Our work indicates that schizophrenic patients with water imbalance have enhanced activity of the hypothalamic-pituitary-adrenal (HPA) axis and the antidiuretic hormone (arginine vasopressin: AVP) in response to psychological stress. Furthermore, these findings appear attributable to hippocampal dysfunction, which may in turn be directly related to the underlying psychiatric disorder. The AVP abnormality likely contributes to life threatening water intoxication and the HPA axis abnormality may be part of a more general hippocampal-mediated vulnerability to psychological stress. Our pilot findings indicate that there is also a deficit in the closely related neurohormone, oxytocin, in these patients that may contribute to enhanced AVP and HPA axis responses to psychological stress, as well as to a particularly virulent form of schizophrenia (i.e. deficit syndrome) characterized by extreme social deficits. The goal of this study is to confirm the putative deficits in oxytocin regulation, and begin to determine the extent that neuroendocrine and behavioral functions can be restored with oxytocin treatment. Aim I will confirm or disprove that oxytocin levels are lower in patients with water imbalance. Aim II will assess the association between plasma oxytocin versus social deficits and the deficit syndrome. Aim III will assess if intranasal oxytocin normalizes the enhanced AVP and HPA axis responses to stress in patients with water balance. Aim IV will determine if intranasal oxytocin ameliorates social deficits in patients with low plasma oxytocin. These exploratory studies are innovative and could directly lead to new therapeutic modalities for intractable and virulent features of severe mental illness. PUBLIC HEALTH RELEVANCE: Schizophrenia is one of the most devastating illnesses known to man. Our efforts to understand and treat this disease are based on recent insights into how hormones regulated by the brain determine our responses to stress and to social situations. We study a group of people with schizophrenia who exhibit abnormalities in the regulation of these hormones, which our data suggest, are related to their poor stress tolerance and impaired emotional judgment. We want to see if we can reverse these deficits by giving one of the hormones (oxytocin) by a nasal spray. This work has the potential to increase our understanding of what causes schizophrenia, as well as to identify novel therapies.